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Background Recurrent moderate hypoglycemia (RH), a major adverse effect of hypoglycemic therapy in diabetic patients, is one of the main risk factors for cognitive impairment and dementia. Transient receptor potential canonical channel 6 (TRPC6) is a potential therapeutic target for Alzheimer's disease (AD) and its expression is highly regulated by glucose concentration. Objective To investigate whether RH regulates the expression of TRPC6 in brain and whether TRPC6 dysfunction can drive hypoglycemia‐associated cognitive impairment in diabetes, and reveal the underlying mechanism. Methods Histological staining, in vivo two‐photon Ca2+ imaging, and behavioral tests were used to measure neuronal death, brain network activity, and cognitive function in mice, respectively. High‐resolution respirometry and transmission electron microscope were used to assess mitochondrial structure and function. Intracellular calcium measurement and molecular biology techniques were conducted to uncover the underlying mechanism. Results Here, we report that the expression of TRPC6 in hippocampus was specifically repressed by RH in streptozocin‐induced type 1 diabetic mice, but not in nondiabetic mice. TRPC6 knockout directly leads to neuron loss, neuronal activity, and cognitive function impairment under diabetic condition, the degree of which is similar to that of RH. Activation of TRPC6 with hyperforin substantially improved RH‐induced cognitive impairment. Mechanistically, TRPC6 inhibited mitochondrial fission in the hippocampus of diabetic mice undergoing RH episodes by activating adenosine 5‘‐monophosphate‐activated protein kinase, and TRPC6‐mediated cytosolic calcium influx was required for this process. Clinically, dysfunction of TRPC6 was closely associated with cognitive impairment in type 2 diabetic patients with RH. Conclusions Our results indicate that TRPC6 is a critical sensitive cation channel to hypoglycemia and is a promising target to prevent RH‐induced cognitive impairment by properly orchestrating the mitochondrial dynamics in diabetic patients., Recurrent moderate hypoglycemia disturbs mitochondrial morphology and function in hippocampus by inhibiting TRPC6, leading to neuronal death and cognitive impairment in diabetic mice.

Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.

High salt intake is a major risk factor for hypertension and is associated with cardiovascular events. Most countries exhibit a traditionally high salt intake; thus, identification of an optimal strategy for salt reduction at the population level may have a major impact on public health. In this multicenter, random-order, double-blind observational and interventional study, subjects with a high spice preference had a lower salt intake and blood pressure than subjects who disliked spicy food. The enjoyment of spicy flavor enhanced salt sensitivity and reduced salt preference. Salt intake and salt preference were related to the regional metabolic activity in the insula and orbitofrontal cortex (OFC) of participants. Administration of capsaicin—the major spicy component of chili pepper—enhanced the insula and OFC metabolic activity in response to high-salt stimuli, which reversed the salt intensity–dependent differences in the metabolism of the insula and OFC. In animal study, OFC activity was closely associated with salt preference, and salty-taste information processed in the OFC was affected in the presence of capsaicin. Thus, interventions related to this region may alter the salt preference in mice through fiber fluorometry and optogenetic techniques. In conclusion, enjoyment of spicy foods may significantly reduce individual salt preference, daily salt intake, and blood pressure by modifying the neural processing of salty taste in the brain. Application of spicy flavor may be a promising behavioral intervention for reducing high salt intake and blood pressure.

Background/Aims: Obesity and high salt intake are major risk factors for hypertension and cardiometabolic diseases. Obese individuals often consume more dietary salt. We aim to examine the neurophysiologic effects underlying obesity-related high salt intake. Methods: A multi-center, random-order, double-blind taste study, SATIETY-1, was conducted in the communities of four cities in China; and an interventional study was also performed in the local community of Chongqing, using brain positron emission tomography/computed tomography (PET/CT) scanning. Results: We showed that overweight/obese individuals were prone to consume a higher daily salt intake (2.0 g/day higher compared with normal weight individuals after multivariable adjustment, 95% CI, 1.2-2.8 g/day, P < 0.001), furthermore they exhibited reduced salt sensitivity and a higher salt preference. The altered salty taste and salty preference in the overweight/obese individuals was related to increased activity in brain regions that included the orbitofrontal cortex (OFC, r = 0.44, P= 0.01), insula (r = 0.38, P= 0.03), and parahippocampus (r = 0.37, P= 0.04). Conclusion: Increased salt intake among overweight/obese individuals is associated with altered salt sensitivity and preference that related to the abnormal activity of gustatory cortex. This study provides insights for reducing salt intake by modifying neural processing of salty preference in obesity.

Enhanced transient receptor potential canonical subtype 3 (TRPC3) expression and TRPC3-mediated calcium influx in monocytes from hypertensive rats and patients are associated with increased blood pressure. Daily salt intake is closely related to hypertension, but the relationship between TRPC3 expression and salt intake has not yet been evaluated in hypertensive patients. Using reverse transcription-polymerase chain reaction, we studied the expression of TRPC3 and TRPC3-related store-operated calcium entry (SOCE) in peripheral blood mononuclear cells (PBMCs) from hypertensive and normotensive control subjects. Measurement of SOCE was performed using the fluorescent dye Fura-2 AM. Participants were divided into a low-salt group (

Background and Aims: Surgical site infection, in particular superficial incision infection, is a common type of complication following abdominal surgery. Negative-pressure wound therapy has been confirmed to reduce the incidence of surgical site infection in various surgeries, but there are few prospective randomized studies into its application to abdominal surgery. Material and Methods: A prospective randomized controlled study was conducted in which patients with abdominal surgery and open surgery were randomly divided into a negative-pressure wound therapy experimental group and a gauze-covering control group. Information about demographic data, type of surgery, surgical sites, incision treatment outcomes, surgical site infection factors, and follow-up was recorded. Results: From May 2015 to December 2015, 71 patients were enrolled in this study, including 33 in the experimental group and 38 in the control group. There were 10 cases of incision complications, all superficial infections, with an incidence of 14.1%. The surgical site infection incidence was statistically different between the experimental and control groups (3.0% vs 23.7%, p = 0.031). Multivariate logistic regression analysis showed that incision length ⩾20 cm increased the surgical site infection incidence (odds ratio value of 15.576, p = 0.004) and that the application of negative-pressure wound therapy reduced the surgical site infection incidence (odds ratio value of 0.073, p = 0.029). Conclusion: Negative-pressure wound therapy can reduce the incidence of surgical site infection in open abdominal surgery.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. Clinical studies indicate that metabolic surgery improves DN; however, the mechanism remains unclear. Here, we report that Roux-en-Y Gastric Bypass (RYGB) surgery significantly blocked and reversed DN without affecting the insulin signaling pathway. This protective role of RYGB surgery is almost blocked by either inhibition or knockout of 5′AMP-activated protein kinase (AMPK) in podocytes. Furthermore, mRNA microarray data reveal that RYGB surgery obviously reduced the gene expression involved in nicotinamide adenine dinucleotide phosphate (NAPDH) synthesis. The expression of a key NADPH synthase, hexose-6-phosphate dehydrogenase (H6PD), was inhibited by the low plasma corticosterone level after surgery. In addition, blocking NAPDH synthesis by knocking down H6PD mimicked the beneficial role of RYGB surgery through activation of AMPK in podocytes. Therefore, this study demonstrates that reducing NADPH production is critical for renal AMPK activation in response to RYGB surgery.

Background Environmental cold‐induced hypertension is common, but how to treat cold‐induced hypertension remains an obstacle. Transient receptor potential melastatin subtype 8 (TRPM8) is a mild cold‐sensing nonselective cation channel that is activated by menthol. Little is known about the effect of TRPM8 activation by menthol on mitochondrial Ca 2+ homeostasis and the vascular function in cold‐induced hypertension. Methods and Results Primary vascular smooth muscle cells from wild‐type or Trpm8 −/− mice were cultured. In vitro, we confirmed that sarcoplasmic reticulum–resident TRPM8 participated in the regulation of cellular and mitochondrial Ca 2+ homeostasis in the vascular smooth muscle cells. TRPM8 activation by menthol antagonized angiotensin II induced mitochondrial respiratory dysfunction and excess reactive oxygen species generation by preserving pyruvate dehydrogenase activity, which hindered reactive oxygen species–triggered Ca 2+ influx and the activation of RhoA/Rho kinase pathway. In vivo, long‐term noxious cold stimulation dramatically increased vasoconstriction and blood pressure. The activation of TRPM8 by dietary menthol inhibited vascular reactive oxygen species generation, vasoconstriction, and lowered blood pressure through attenuating excessive mitochondrial reactive oxygen species mediated the activation of RhoA/Rho kinase in a TRPM8‐dependent manner. These effects of menthol were further validated in angiotensin II–induced hypertensive mice. Conclusions Long‐term dietary menthol treatment targeting and preserving mitochondrial function may represent a nonpharmaceutical measure for environmental noxious cold–induced hypertension.

Background Mitochondrial Ca 2+ homeostasis is fundamental to the regulation of mitochondrial reactive oxygen species ( ROS ) generation and adenosine triphosphate production. Recently, transient receptor potential channel, canonical type 3 ( TRPC 3), has been shown to localize to the mitochondria and to play a role in maintaining mitochondrial calcium homeostasis. Inhibition of TRPC 3 attenuates vascular calcium influx in spontaneously hypertensive rats ( SHR s). However, it remains elusive whether mitochondrial TRPC 3 participates in hypertension by increasing mitochondrial calcium handling and ROS production. Methods and Results In this study we demonstrated increased TRPC 3 expression in purified mitochondria in the vasculature from SHR s, which facilitates enhanced mitochondrial calcium uptake and ROS generation compared with Wistar‐Kyoto rats. Furthermore, inhibition of TRPC 3 by its specific inhibitor, Pyr3, significantly decreased the vascular mitochondrial ROS production and H 2 O 2 synthesis and increased adenosine triphosphate content. Administration of telmisartan can improve these abnormalities. This beneficial effect was associated with improvement of the mitochondrial respiratory function through recovering the activity of pyruvate dehydrogenase in the vasculature of SHR s. In vivo, chronic administration of telmisartan suppressed TRPC 3‐mediated excessive mitochondrial ROS generation and vasoconstriction in the vasculature of SHR s. More importantly, TRPC 3 knockout mice exhibited significantly ameliorated hypertension through reduction of angiotensin II –induced mitochondrial ROS generation. Conclusions Together, we give experimental evidence for a potential mechanism by which enhanced TRPC 3 activity at the cytoplasmic and mitochondrial levels contributes to redox signaling and calcium dysregulation in the vasculature from SHR s. Angiotensin II or telmisartan can regulate [Ca 2+ ] mito , ROS production, and mitochondrial energy metabolism through targeting TRPC 3.

The pathogenesis of hypertension remains elusive. Current treatments on hypertension have only achieved modest reductions. Facilitating theoretical research and looking for new therapeutic strategy are urgently needed. Besides food digestion and nutrients absorption, the gastrointestinal tract (GI) has been shown to influence the status of the central nervous system, immune system, metabolism, and cardiovascular homeostasis. Emerging findings demonstrate that endogenous factors derived from GI including gut hormones, autonomic nerve, and gut microbiota play important roles in the regulation of vascular function and/or blood pressure. Meanwhile, evidences from clinical practice and experimental study have found that intervention in GI through metabolic surgery, probiotics consumption, and dietary modification can efficiently ameliorate or even remit hypertension and related cardiometabolic diseases. Thus, we propose that GI might be an initiating organ of hypertension and a promising target for the management of hypertension. Further, illuminating this concept may aid to understand the pathogenesis and control of hypertension.

Background Metabolic syndrome has received great attention because it poses a potential cardiovascular hazard, which increases the risk of lower extremity atherosclerosis. However, the relationship between the components of metabolic syndrome and the onset of chronic venous disorder of the lower extremities remains unexplained. Methods This study investigated the characteristics of cardiometabolic risk factors of early chronic venous disorder of the lower extremities in subjects with cardiometabolic risk. The characteristics of risk factors and diabetes-related complications in diabetic patients with early chronic venous disorder of the lower extremities were also investigated. In addition, the association between early chronic venous disorder and atherosclerosis of the lower extremities was analysed. The study examined 782 subjects with cardiometabolic risk factors, including obesity, hypertension, diabetes mellitus and dyslipidaemia. Lower extremity venous function was measured by digital photoplethysmography. Results Women had a higher prevalence of early chronic venous disorder than did men (p

Aims Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline. Methods We searched the major databases for published or unpublished RCTs that had been performed in patients with T2DM and compared the effects of exenatide and liraglutide to those of other common drugs used to treat T2DM. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis. Results A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of −5.24 and −3.46 mmHg, respectively, and with 95% confidence intervals (CI) of −6.88 to −3.59, p

High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dahl-S) rats were fed with high salt diet with or without 0.1% caffeine in drinking water for 15 days. The BP, heart rate and locomotor activity of rats was analyzed and urinary sodium excretion was determined. The renal epithelial Na+ channel (ENaC) expression and function were measured by in vivo and in vitro experiments. Chronic consumption of caffeine attenuates hypertension induced by high salt without affecting sympathetic nerve activity in Dahl-S rats. The renal α-ENaC expression and ENaC activity of rats decreased after chronic caffeine administration. Caffeine increased phosphorylation of AMPK and decrease α-ENaC expression in cortical collecting duct cells. Inhibiting AMPK abolished the effect of caffeine on α-ENaC. Chronic caffeine intake prevented the development of salt-sensitive hypertension through promoting urinary sodium excretion, which was associated with activation of renal AMPK and inhibition of renal tubular ENaC.

OBJECTIVES Obesity and hypertension are associated with an adverse metabolic profile and systemic low-grade inflammation. Metformin reduces weight and inflammation in patients with diabetes, but it is unclear whether it has beneficial effects in patients without diabetes. The objective was to explore whether metformin-based treatment could benefit obesity-related hypertension without diabetes. METHODS A randomized, double-blind, placebo-controlled factorial trial was conducted in 360 obese hypertensive patients without diabetes in Chongqing, China. After a 1-2-week run-in period, patients were randomly assigned to metformin (500 mg once per day) or placebo, as well as to an antihypertensive medication. Change in blood pressure, obesity measurements and metabolic profile were assessed at 24 weeks. RESULTS The 180 participants randomized to metformin and 180 randomized to placebo were similar at baseline. At 24 weeks, metformin compared with placebo did not have significant effects on blood pressure, blood glucose, high-density or low-density lipoprotein cholesterol, but it did reduce total serum cholesterol (0.2 mmol/l, P = 0.038). Metformin also significantly reduced weight (-0.7 kg, P = 0.006), BMI (-0.2 kg/m, P = 0.024), waist circumference (-0.9 cm, P = 0.008), and both subcutaneous (-6.1 cm, P = 0.043) and visceral adiposity (-5.4 cm, P = 0.028) as measured by computed tomography, and lowered serum high-sensitivity C-reactive protein levels (-0.6 mg/dl, P < 0.001). There was no significant difference in adverse events (P = 0.785). CONCLUSIONS Metformin has no effect on blood pressure and blood glucose levels, but it does reduce total cholesterol, abdominal obesity and C-reactive protein levels in obese hypertensive patients without diabetes.

Vascular endothelial dysfunction has been demonstrated in metabolic syndrome (MS). Chronic administration of rosiglitazone ameliorates endothelial dysfunction through PPARγ-mediated metabolic improvements. Recently, studies suggested that single dose of rosiglitazone also has direct vascular effects, but the mechanisms remain uncertain. Here we established a diet-induced rat model of MS. The impaired vasorelaxation in MS rats was improved by incubating arteries with rosiglitazone for one hour. Importantly, this effect was blocked by either inhibition of PPARγor PPARδ. In cultured endothelial cells, acute treatment with rosiglitazone increased the phosphorylation of Akt and eNOS and the production of NO. These effects were also abolished by inhibition of PPARγ, PPARδ, or PI3K. In conclusion, rosiglitazone improved endothelial function through both PPARγ- and PPARδ-mediated phosphorylation of Akt and eNOS, which might help to reconsider the complex effects and clinical applications of rosiglitazone.

BACKGROUND Salt-induced vascular dysfunction in which underlying mechanisms involve reactive oxygen species (ROS)-mediated reduction of nitric oxide (NO) bioavailability has been well documented. Uncoupling protein 2 (UCP2) has been implicated in the vascular protection, specifically by decreasing ROS production. However, it is unclear how UCP2 affects vascular function in salt-loaded mice. METHODS UCP2-deficient (UCP2 -/- ) and wild-type (WT) mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. Blood pressure (BP), mesenteric arterial reactivity, superoxide production, and NO bioavailability in the intact vessels were measured in each group. RESULTS UCP2 -/- mice on a HS diet had a higher BP than those on a NS diet (P < 0.01). However, BP in WT mice was not different between the NS and HS diet group. Phenylephrine (PE)-induced contraction was enhanced while acetylcholine (ACh)-elicited relaxation was impaired in mesenteric resistance arteries from the HS diet-fed WT mice. Importantly, the enhanced contraction and impaired relaxation were both further exacerbated in UCP2 -/- mice. Similarly, the HS diet led to a moderate increase in superoxide production and a comparable decrease in NO availability in both aortas and mesenteric resistance vessels, and these effects were also remarkably enhanced in UCP2 -/- mice. CONCLUSIONS These findings suggest that UCP2 plays an important role in preventing salt-sensitive hypertension, which may be achieved by suppressing superoxide production and reserving NO bioavailability in blood vessels.

This study investigates the sex difference of cardiometabolic risk profiles in subjects with visceral fat obesity (VFO) but normal waist circumference (WC). VFO, which is defined as visceral adipose tissue (VAT) area more than 100 cm(2) by computed tomography (CT), and cardiometabolic risk profiles were assessed in 437 subjects with normal WC (197 female subjects and 240 male subjects). The expression of adiponectin and its receptor in abdominal adipose tissue was measured in a subgroup of the subjects. Compared with the male subjects, female subjects had a larger abdominal subcutaneous adipose tissue (SAT) area (158+/-56 vs 116+/-38 cm(2), P0.01), smaller VAT area (67+/-44 vs 78+/-33 cm(2); P0.01), and lower prevalence of VFO (12.2 vs 24.2%, P0.001). This finding was accompanied by upregulated expressions of adiponectin and its receptor in abdominal adipose tissue in female subjects. Without VFO, the risk profiles were not significantly different between male subjects and female subjects. Although risk factors were increased and intensified in both sexes in the presence of VFO, female subjects with VFO were associated with greater cardiometabolic risks than male subjects. A regression analysis indicates the ratio of VAT/SAT for female subjects, whereas VAT and age for male subjects were independently associated with clustering of multiple cardiometabolic risk factors. In conclusion, in subjects with normal WC, the prevalence of VFO is lower and the expression of adiponectin and its receptor is higher in female subjects compared with male subjects. Although VFO was associated with increased risk in both sexes, the risk profile in female subjects with VFO was more pronounced.

Observational studies established high-sensitivity C-reactive protein as a risk factor for cardiovascular events in the general population. The goal of this study was to determine the relationship between target organ damage and high-sensitivity C-reactive protein in a cohort of Chinese patients with metabolic syndrome. A total of 1082 consecutive patients of Chinese origin were screened for the presence of metabolic syndrome according to the National Cholesterol Education Program's Adult Treatment Panel III. High-sensitivity C-reactive protein and target organ damage, including cardiac hypertrophy, carotid intima-media thickness, and renal impairment, were investigated. The median (25th and 75th percentiles) of high-sensitivity C-reactive protein in 619 patients with metabolic syndrome was 2.42 mg/L (0.75 and 3.66 mg/L) compared with 1.13 mg/L (0.51 and 2.46 mg/L) among 463 control subjects (P.01). There was a progressive increase in high-sensitivity C-reactive protein level with the number of components of the metabolic syndrome. Stratification of patients with metabolic syndrome into 3 groups according to their high-sensitivity C-reactive protein concentrations (1.0, 1.0-3.0, and3.0 mg/L) showed that the subjects with the elevated high-sensitivity C-reactive protein had a higher percentage of target organ damage than those with lower high-sensitivity C-reactive protein. Stepwise multiple logistic regression confirmed that high-sensitivity C-reactive protein was significantly associated with cardiac hypertrophy, carotid intima-media thickness, and renal impairment. The study shows a strong independent association between inflammation and target organ damage in a large cohort of patients of Chinese origin with metabolic syndrome.

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H 2 S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H 2 S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression of hydrogen sulfide–synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3–mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

Background The prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation. Whether TRPV1-evoked alterations in Cx43-mediated adipocyte-to-adipocyte communication play a role in obesity is unknown. Materials and methods We investigated whether Cx43 participated in TRPV1-mediated adipocyte lipolysis in cultured 3T3-L1 preadipocytes and visceral adipose tissues from humans and wild-type (WT) and TRPV1-deficient (TRPV1-/-) mice. Results TRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. Long-term chronic dietary capsaicin decreased the body weights and serum lipids of WT mice, but not TRPV1-/- mice, fed a high-fat diet. Conclusion This study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo. TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.

Objective: Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to improve metabolic status in animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human, especially in prehypertensive participants. Design and Method: In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on metabolic parameters, such as blood pressure (BP) levels, carotid intima-media thickness (IMT), ankle brachial index (ABI)/toe brachial index (TBI), BMI and biochemical parameters in prehypertensive participants. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Then we further validated the results in spontaneously hypertensive rats (SHR), which were were intervented with 2% taurine water for 12 weeks. Results: Totally 97 participants completed the trial and no significant difference observed between the taurine and placebo groups. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. In addition, taurine supplementation significantly improved endothelium-dependent and -independent vasodilation and reduced IMTs of these prehypertensive participants. Meanwhile taurine intervention increased plasma H2S and taurine concentrations. Other parameters did not change significantly upon taurine treatment compared with pre-treatment or placebo group. To further elucidate the mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment exerts hypotensive effects by upregulating the expressions of H2S-synthesizing enzymes and reducing agonist-induced vascular reactivity through the inhibition of TRPC3-mediated calcium influx in human and mouse mesenteric arteries. Also, taurine reduced ROS levels and improved mitochondrial respiratory fucntions in VSMCs from SHR compared with control group, thus inhibiting vascular remodeling pathways. Conclusions: Taurine supplementation improved vascular function of prehypertensive participants and SHRs by lowering BP levels and reducing IMT values. Taurine may become a new dietary factor improving the metabolic status in prehypertension.

Background We investigated the hypothesis that the favorable effects of gastrointestinal ( GI ) intervention on hypertension ( HTN ) and cardiovascular ( CV ) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system ( SNS ). Methods and Results Hypertensive patients with metabolic disturbances underwent laparoscopic Roux‐en‐Y gastric bypass surgery, and spontaneously hypertensive rats ( SHR s) underwent RYGB or sham surgery. Blood pressure ( BP ), heart rate ( HR ), endothelium‐dependent flow‐mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow‐up. Changes of BP and HR in response to cold stress, renal sympathetic nervous activity ( RSNA ), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract ( NTS ), and CV function and structure were examined in SHR s with or without surgery. Compared with baseline, BP and HR were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial‐dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery. CV disturbances were reversed by surgery in SHR s. Under acute cold exposure, the variations in BP and HR were smaller in surgically treated SHR s, compared to sham SHR s. RSNA and vasoconstriction induced by perivascular nerve stimulation as well as NTS ‐mediated changes of BP were decreased in surgically treated SHR s, compared to sham SHR . Weight loss did not affect BP and RSNA in sham SHR s. Conclusions GI intervention ameliorates HTN in both hypertensive patients and rats by inhibiting overdrive of the SNS . Therefore, targeting gastrointestine could be a novel strategy to treat HTN with metabolic disturbances.

High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptorsδ(PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardiac hypertrophy and fibrosis and the effect of cross-talk between TRPV1 and PPAR-δon suppressing high-salt diet-generated oxidative stress. In this study, high-salt diet-induced cardiac hypertrophy and fibrosis are characterized by significant enhancement of HW/BW%, LVEDD, and LVESD, decreased FS and EF, and increased collagen deposition. These alterations were associated with downregulation of PPAR-δ, UCP2 expression, upregulation of iNOS production, and increased oxidative/nitrotyrosine stress. These adverse effects of long-term high-salt diet were attenuated by chronic treatment with capsaicin. However, this effect of capsaicin was absent in TRPV1−/−mice on a high-salt diet. Our finding suggests that chronic dietary capsaicin consumption attenuates long-term high-salt diet-induced cardiac hypertrophy and fibrosis. This benefit effect is likely to be caused by TRPV1 mediated upregulation of PPAR-δexpression.

Recent studies indicate that transient receptor potential canonical type 3 (TRPC3) channels contribute to the regulation of blood pressure and vascular and renal function. Several studies show that TRPC3 dysfunction is associated with hypertension, atherosclerosis, cardiac hypertrophy, and cerebrovascular events. In this review, we summarize the role of TRPC3 channels in the cardiovascular system, and we focus on their pathophysiogical role in hypertension and related target organ damages. We provide new insight into the involvement of TRPC3 channels in the development of hypertension and its related complications.

The activation of nuclear factor (NF)-κB by cytokines under hyperglycaemic conditions is a potential mechanism for complications in diabetes. We investigated whether small ubiquitin-like modifier 4 (SUMO4) regulates renal NF-κB signalling in diabetic rats. Histological changes in kidney were analysed in diabetic GK rats. The expressions of tumour necrosis factor (TNF)-α, NF-κB (p65), IκBα and SUMO4 in renal tissues were examined by immunohistochemistry and Western blotting. Primary cultured glomerular endothelial cells from rats were stimulated by TNF-α or interleukin (IL)-2. The renal expression of TNF-α, NF-κB (p65), IκBα and SUMO4 was significantly higher in diabetic GK rats than in control rats. In control rats, no nuclear translocation was observed for IκBα or NF-κB (p65). However, in diabetic GK rats, translocation of NF-κB (p65) and IκBα into the nucleus was observed, and the expression of SUMO4 and IκBα was up-regulated in the glomerular endothelial cells. SUMO4 was localised in both the cytoplasm and nucleus, while IκBα was predominantly located in the nucleus after stimulation with TNF-α. In contrast, SUMO4 was localised in the nucleus, and increased cytoplasm SUMO4 localisation was found after stimulation with IL-2. SUMO4 plays a role in regulating NF-κB signalling in glomerular cells. Cytokines have a unique effect in regulating the sumoylation of NF-κB.

Background and Purpose— Previous studies show that endothelial nitric oxide synthase (eNOS) plays a prominent role in maintaining cerebral blood flow and preventing stroke. Capsaicin in hot pepper can increase the phosphorylation of eNOS in endothelial cells. We test the hypothesis that chronic dietary capsaicin can prevent stroke through activation of cerebrovascular transient receptor potential vanilloid 1 (TRPV1) channels in stroke-prone spontaneously hypertensive rats (SHRsp). Methods— SHRsp were fed dietary capsaicin, and their onset of stroke was examined. TRPV1 knockout and transgenic mice were used for determining the function of TRPV1 channels. Expression of eNOS and cerebrovascular reactivity were examined. Results— Immunofluorescence showed TRPV1 channels and eNOS coexpression in cerebral arterioles. Administration of capsaicin significantly increased phosphorylated eNOS in carotid arteries from wild-type mice but not in TRPV1 knockout mice. Inhibition of eNOS using N G -nitro- l -arginine methyl ester, removal of endothelium, or mutant TRPV1 significantly reduced capsaicin-induced endothelium-dependent relaxation of basilar arteries in mice. Chronic dietary capsaicin also remarkably increased eNOS expression in carotid arteries from SHRsp. Compared with Wistar-Kyoto rats, SHRsp had impaired endothelium-dependent relaxation of basilar arteries. Administration of capsaicin or l -arginine significantly improved the endothelium-dependent relaxation of basilar arteries in SHRsp. SHRsp had hypertrophy of cerebral arterioles, which was reversed by dietary capsaicin. Importantly, long-term administration of capsaicin significantly delayed the onset of stroke and increased the survival time in SHRsp. Conclusions— Activation of TRPV1 channels by dietary capsaicin mediated increases in phosphorylation of eNOS and could represent a novel target for dietary intervention of stroke.

The role of nonselective cation channels of the transient receptor potential channel (TRPC) family in essential hypertension has not yet been investigated.We studied TRPCs in 51 patients with essential hypertension and 51 age-matched and sex-matched normotensive control subjects. Calcium and gadolinium influx into human monocytes was determined using the fluorescent dye technique. TRPC expression was measured using reverse transcriptase-polymerase chain reaction and in-cell western assay. Gene silencing by small interfering RNA for specific TRPC knockdown was also performed.We observed an increased gadolinium/calcium-influx ratio through TRPC in essential hypertensive patients compared with normotensive control subjects [cation influx ratio (mean +/- SEM), 125 +/- 14 versus 80 +/- 7%; each n = 51; P0.01], due to an increase of gadolinium influx in hypertensive patients compared with normotensive control subjects (48 +/- 4 versus 36 +/- 3%; each n = 51; P0.05). We observed a significant increase of TRPC3 and TRPC5 protein expression in essential hypertensive patients compared with normotensive control subjects (normalized TRPC3 expression, 3.21 +/- 0.59 versus 1.36 +/- 0.07; each n = 20; P0.01; normalized TRPC5 expression, 2.10 +/- 0.28 versus 1.40 +/- 0.52; each n = 12; P0.05). We used small interfering RNA for knockdown of TRPC5. The thereby reduced channel expression caused a significant attenuation of calcium and gadolinium influx.This study points to an important role of TRPCs in essential hypertension.

Background Sodium-induced hypertensive cardiac hypertrophy is related to pressure and volume overload. Methods Wistar rats were exposed to low and high sodium diet for 8 weeks. Angiotensin II receptor mRNA, abundance of p38 mitogen-activated protein kinase (p38MAPK), vasoconstriction of aortic rings, and angiotensin II-induced calcium increase were investigated. Results Rats on high sodium diet showed significantly elevated blood pressure. Heart weight, AT1 receptor mRNA in cardiac and aortic tissues, and abundance of p38MAPK were significantly increased in rats on high sodium diet. Conclusions Increased AT1 receptor expression and angiotensin II-induced calcium increase are compensatory effects in sodium-induced hypertension.